遗传学分析引发癌症治疗临床试验变革

布鲁塞尔——随着癌症相关遗传标志物的队伍迅速壮大，肿瘤治疗临床试验的设计正在发生根本性的转变。如今的趋势是将详细的遗传学分析纳入到临床试验中，这样一旦有了结果，研究者就可以尝试将治疗应答或失败与肿瘤遗传特性的变化联系起来。

在由美国临床肿瘤学会(ASCO)、欧洲癌症研究与治疗组织(EORTC)和美国国立癌症研究所(NCI)联合举办的会议上，这一领域的权威专家指出，理想的情况是，对参加癌症治疗临床试验的每例患者的肿瘤都进行基线遗传学分析，可使用包含靶向遗传标志物的大型试剂盒，也可使用全基因组测序。不过他们承认，目前全基因组测序提供的信息绝大多数都没有实用价值。

癌症治疗临床试验设计的这种范式变化伴随着一个明显的内在局限性，即似乎只有极大地增加参加试验的患者范围才能解决问题：每一个突变癌症“驱动因素”似乎都只对少数患者特异。这意味着要想在患者对不同药物的应答和他们的肿瘤遗传学特征之间建立起联系，需要筛选成千上万的患者，远远超过了当今治疗临床试验的一般招募规模。

“最大的挑战是确定有助于报告临床试验结果的突变或基因改变。目前有很多潜在的遗传标志物，但其中只有很少已得到验证。”纽约大学乳腺肿瘤内科项目主任Francisco J. Esteva博士在接受采访时指出：“我们正在对肿瘤进行测序，已发现了大量突变；但是我们对其中绝大多数信息仍然不知该如何使用。”

“通过下一代测序找出‘可加以干预’突变是非常复杂的。我们有一些很棒的针对特定突变的抑制剂药物，对经过选择的患者非常有效，但当我们在更大的患者群中使用这些药物时却可能效果不佳。”

尽管一个肿瘤可能携带着一种被确认是致癌因素的突变基因，后者对于部分患者而言是有效的药物治疗靶点，但这种突变可能并不是其他患者的最重要的肿瘤驱动因素。

“试着找出可作为治疗靶点的突变或其他遗传学改变，这听起来很简单，但实际则不然。”北卡罗来纳大学教堂山分校乳腺中心主任Lisa A. Carey博士指出：“我们一直习惯于每次研究1种遗传标志物，然而如今这种方式显然已无法满足我们的需求了。”


Shivaani Kummar博士

“观察肿瘤的全基因谱很有吸引力，但也更复杂。目前，我们掌握的具有已知临床意义的遗传标志物和药物还很有限。我们在靶向治疗方面已经取得了巨大成功，但它并不简单，离彻底解决问题还远得很。”NCI癌症治疗与诊断部的Shivaani Kummar博士指出：“在一个肿瘤中找到靶点，并找出可抑制这个靶点的药物，并不一定能带来临床益处。”

美国食品药品管理局(FDA)器械与放射卫生中心首席医学官Robert L. Becker Jr.博士指出：“下一代测序可以为我们提供海量遗传信息，从而使我们有可能以相对可承受的成本获得成百上千种基因的相关数据。这一现状正影响着试验设计，催生出了‘伞状’设计，即运用多种遗传标志物和数种药物。”


Robert L. Becker, Jr.博士

“目前研发诊断性标志物和药物的模式是否具有可持续性？”Becker博士问道：“下一代测序是不同的，因为它可以在单次检测中查询几乎无限数量的分析物。”

在本次会议上，来自美国和欧洲多位研究者描述和讨论了最近设计的药物治疗临床试验，这些试验采用了前瞻性的结构，以便从入组患者中采集广泛的遗传数据。

MATCH(治疗选择的分子分析)就是一项这样的试验，预计将在2014年启动，计划招募约1,000例在接受至少1种药物初始治疗后发生进展的实体肿瘤患者。Kummar博士介绍，将使用定向突变或扩增以及全外显子组测序，以期更好地为患者安排后续治疗方案。

Esteva博士表示：“这是一种新的癌症治疗临床试验的设计范式。展望未来，所有重要的药物临床试验的设计都应当包括遗传学分析。”

不过，包括MATCH试验在内的多项试验都将需要进行大范围筛选，以找到足够数量的合格患者。“每种突变的携带者都是一个小的子集，因此要想达到获取治疗相关信息所需的样本量将必须借助社区的力量。从在学术中心对相对较少的患者开展研究，发展到由社区肿瘤医生治疗大量患者，将是一个最大的挑战。”

将常规遗传学分析融入临床试验和常规实践中，还会带来其他问题。Carey博士指出：“肿瘤在治疗过程中会发生变化，所以基线检查发现的肿瘤和我们治疗的肿瘤可能不是一个东西？”

一旦肿瘤遗传学分析成为常规，另一个挑战将是，当研究者发现原本临床后果不明的遗传标志物可以被某种靶向药物有效治疗的时候，如何有效、准确地提醒医生和患者。

而且，在直接活检样本和从患者血液中采集的肿瘤细胞或肿瘤DNA中，我们尚不确定哪一种是遗传学分析的更好对象。

当下，关键是要使遗传学分析成为每一项癌症治疗临床试验的常规组成部分。“我们需要对每一例患者进行肿瘤分析，应当确定所有类型癌症的相关因素。”

Becker博士、Carey博士、Esteva博士和kummar博士均报告称无相关利益冲突。

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By: MITCHEL L. ZOLER, Internal Medicine News Digital Network

BRUSSELS – The ballooning list of genetic markers linked with various cancers is spawning a radical shift in the design of oncology treatment trials.

These days, the trend is to incorporate detailed genetic analysis into the trials, so that once the results are in, researchers can try to correlate treatment responses or failures with variations in each tumor’s genetic profile.

Leaders in the field say that, ideally, the tumor of every single patient now entering a cancer treatment trial should undergo a baseline genetic analysis, either using a large panel of targeted genetic markers or full-genome sequencing – although they acknowledge that, for the time being, complete sequencing provides much more information than can be used practically.

This changing paradigm of cancer treatment trial design comes with a major, built-in limitation that seems solvable only by dramatically increasing the scope of patients enrolled in trials: Each mutational cancer "driver" seems specific for just a few percent of patients.

That means making statistically meaningful correlations among the responses of patients to various drugs and their tumors’ genetic profiles requires sifting through thousands of patients, far more than usually enroll in treatment trials today.

"The big challenge is to identify the mutations or genetic alterations that help inform the results of clinical trials. There are a lot of potential genetic markers, but very few have been validated.

Tumors are being sequenced, and we find lots of mutations; but we don’t yet know what to do with most of this information," said Dr. Francisco J. Esteva, professor of medicine and director of the breast medical oncology program at New York University in an interview during a meeting on markers in cancer.

"Finding ‘actionable’ mutations is very complicated because of next-generation sequencing," Dr. Esteva added. "We have some very good inhibitor drugs" aimed at certain mutations that can be highly effective in selected patients, "but when we give these drugs to larger populations of patients, the drugs may not work."

Even though a tumor may carry a genetic mutation identified as a cancer driver and thus an effective target for drug treatment in some patients, the mutation may not be the most important driver in other patients.

"Trying to find the mutations or other genetic changes that can be effective targets for treatment sounds simple, but it’s really not so simple," noted Dr. Esteva, an organizer of the meeting, sponsored by the American Society of Clinical Oncology, the European Organization for Research and Treatment of Cancer, and the National Cancer Institute.

"We’ve been in an era where we looked at one genetic marker at a time. Now it’s pretty clear that this approach will not move us forward fast enough," said Dr. Lisa A. Carey, professor and medical director of the breast center at the University of North Carolina in Chapel Hill, and another organizer of the meeting.

"Looking at a full genetic profile of the tumor has great appeal but is also more complicated," Dr. Carey explained. "Today, we have a limited portfolio of genetic markers with known clinical significance and a limited portfolio of drugs. We’ve had some huge success stories [with targeted therapy], but it’s not simple, and it is far from solved."

"Finding a target in a patient’s tumor and having an agent that inhibits the target does not imply clinical benefit," said Dr. ShivaaniKummar, head of early clinical trials development in the division of cancer treatment and diagnosis of the National Cancer Institute.

The enormous volume of genetic information now available from next-generation sequencing, which can supply data on hundreds or even potentially thousands of individual genes for a relatively affordable price, "is affecting trial design, leading to ‘umbrella’ designs that use a variety of genetic markers and panels of several drugs," said Dr. Robert L. Becker Jr., a chief medical officer at the Center for Devices and Radiological Health of the Food and Drug Administration.

"Is the current model for development of diagnostic markers and drugs sustainable?’" Dr. Becker asked. "Next-generation sequencing is different, because it can query an almost unlimited number of analytes in a single assay."

At the meeting, a series of researchers from the United States and Europe described and discussed several recently designed drug treatment trials prospectively structured to collect wide-ranging genetic data from the tumors of enrolled patients.

One example is the MATCH (Molecular Analysis for Therapy Choice) trial, expected to start in 2014 with a goal of enrolling about 1,000 patients with solid tumors that have progressed following initial treatment with at least one drug. The investigators will use targeted mutations or amplifications as well as whole exome sequencing to try to better assign patients to their next regimen, said Dr. Kummar.

"It’s a new paradigm of trial design for cancer," said Dr. Esteva. "Going forward, all major drug trials should be designed" to include genetic analyses.

But the MATCH trial, as well as several others outlined at the meeting, will require casting large nets to find adequate numbers of appropriate patients to enroll.

"It’s a small subset of patients with each type of mutation, so getting the sample size required to get information about treatments will require a community effort," said Dr. Esteva. "It’s very important to have a lot of patients to get meaningful results." Progressing from studies with relatively small numbers of patients at academic centers to the larger populations of patients treated by community oncologists "will be one of the biggest challenges," he said.

Incorporating routine genetic analyses into trials and into routine practice also raises other issues, Dr. Carey noted. "Does the tumor evolve during treatment, so that what was found with testing at baseline is no longer the disease being treated?"

Once genetic profiling of tumors becomes routine, another challenge will be efficiently and reliably alerting physicians and patients when a genetic marker that had no known clinical consequence when it was first found in a patient’s tumor is subsequently discovered to be effectively treated with a targeted drug, she said.

And no consensus has emerged on whether it’s best to do genetic assessments of tumors using specimens collected by direct biopsy or by collecting tumor cells or tumor DNA circulating in a patient’s blood, Dr. Carey cautioned.

For now, the key step is making genetic analysis a routine part of every cancer-treatment trial. "We need tumor analyses for every patient," she said. "We should get correlates for 100% of cancers."

Dr. Becker, Dr. Carey, Dr. Esteva, and Dr. Kummar all said that they had no disclosures.